Mabthera-RA 2010

For over 20 years, RA has been considered to be a T cell-mediated disease. Recent evidence, however, has sparked a strong interest in B cells and their key role in the pathogenesis of RA.

Although the underlying causes of RA remain elusive, B cells have been shown to play at least three critical roles in the pathophysiology of RA:

B cells can function as antigen-presenting cells, leading to T cell activation.

B cells present in the RA synovial membrane may secrete a range of pro-inflammatory cytokines, some of which are components in the process leading to joint inflammation and damage.

B cells produce auto-antibodies such as rheumatoid factor (RF). In the synovium, RF immune complexes may mediate complement activation and the propagation of the inflammatory cascade.

References: Lund et al. 2005; Silverman and Carson 2003.

MabThera^® is the first and only selective B cell-targeted therapy for RA. It is a genetically engineered, chimeric monoclonal antibody that selectively targets the subset of B cells that express the CD20* protein, leaving stem cells, pro-B cells and plasma cells unaffected.

After MabThera^® binds to CD20, depletion of CD20-positive B cells by MabThera^® occurs by three possible mechanisms:

Initiation of complement-mediated B cell lysis. The complex of MabThera^® with CD20 initiates the complement cascade, activating the membrane attack complex, which results in the lysis of CD20-positive B cells.

Initiation of cell-mediated cytotoxicity. Natural killer cells, macrophages and monocytes are recruited through the human-derived portion of MabThera^® when it is bound to CD20, inducing CD20-positive B cell lysis.

Promotion of CD20-positive B cell apoptosis. Apoptosis (programmed cell death) may be induced by the binding of MabThera^®, leading to CD20-positive B cell lysis.

*CD = cluster of differentiation

References: Clynes et al. 2000; Golay et al. 2000

The efficacy and safety of the combination of MabThera^® with DMARDs other than methotrexate remain to be investigated.

MabThera^® as monotherapy has been shown to be more effective than methotrexate alone, although the efficacy of MabThera^® is more pronounced and better sustained when used in combination with methotrexate. MabThera^® is approved for use in combination with methotrexate.

The efficacy of MabThera^® monotherapy was investigated in the Phase IIa study in a limited number of patients (n=40). Of these patients, 65% achieved an ACR20 response compared with 38% of patients receiving methotrexate (p=0.025). At the ACR50 level (the primary endpoint of the trial), the proportion of patients responding was higher in the MabThera^® monotherapy group than in patients continuing on methotrexate (33% versus 13%); this difference approached, but did not achieve, statistical significance (p=0.059).

Reference: Edwards et al. 2004

Before MabThera^® emerged as an active treatment for patients with RA, it had been used extensively in patients with B cell malignancies such as non-Hodgkin’s lymphoma (NHL). In dose-finding studies in NHL, four doses of 375 mg/m² (body surface area) was found to be a safe and effective regimen for B cell depletion, although there was no clear dose response. For an average adult with NHL this equates to a total dose of 2400–2800 mg.

The total dose in RA is 2000 mg (2 x 1000 mg), slightly lower than in NHL. This is not surprising because NHL patients are likely to require more antibody to remove the additional burden of tumour cells. In clinical trials the 2 x 1000 mg regimen showed an overall trend towards greater proportions of patients achieving high efficacy endpoints compared to the 2 x 500 mg dose. For this reason the 1000 mg dose was chosen for further development.

Reference: Emery et al., 2006

A course of MabThera^® consists of two 1000 mg intravenous infusions. The recommended dosage of MabThera^® is 1000 mg by intravenous infusion followed by a second 1000 mg intravenous infusion two weeks later. There is no need to adjust for patient body weight or surface area and no dose adjustment is required in elderly patients (aged >65 years). Please see the Summary of Product Characteristics for full dosage and administration information.

In clinical trials of MabThera^® at different doses a significant dose-response effect has not been observed, but patients treated with 2 x 1000 mg achieved numerically higher responses than those treated at lower doses such as 2 x 500 mg.

Reference: Emery et al., 2006

The same as the initial course: 2 infusions of MabThera^® 1000 mg administered 2 weeks apart.

This regimen has been shown to maintain or further improve clinical response in patients receiving further courses of MabThera^®.

References: De Vita et al. 2006; Emery et al. 2006; Keystone et al. 2006; Tak et al. 2006; van Vollenhoven et al. 2006

In an open-label long term follow up study, patients received subsequent courses of MabThera^® as needed according to the treating clinician’s assessment of disease activity and irrespective of the peripheral B lymphocyte count. The time interval between courses was variable, with the majority of patients receiving further therapy 6-12 months after the previous course. Some patients required even less frequent repeat treatment. The response to further therapy was at least the same magnitude as that following the initial treatment course.

The limited clinical trial data on multiple courses of MabThera^® used to treat RA seem to be associated with a similar adverse event profile to that observed following first exposure. Human anti-chimeric antibodies (HACA) develop in some patients after the first course of MabThera^®. The presence of HACA may be associated with the worsening of infusion or allergic reactions after the second infusion of subsequent courses.

Disease activity in the patient should be regularly monitored and the benefit/risk balance of therapy with MabThera^® should be carefully considered before administering subsequent courses. If a repeat course of treatment is considered it should not be given at an interval less than 16 weeks. Please see the Summary of Product Characteristics for full dosage and administration information.

Reference: Keystone et al., 2007

Infusion reactions with MabThera^® are mainly mild–moderate, easily managed and reduce with further infusions.

In most cases, the infusion can be temporarily interrupted and subsequently resumed at a slower (50%) rate when all symptoms have completely resolved.

In the event of a severe reaction, infusion of MabThera^® should be stopped immediately and patients should receive aggressive symptomatic treatment.

The first infusion of each course lasts 4 hours 15 minutes. The second infusion of each course lasts 3 hours 15 minutes.

MabThera^® Summary of Product Characteristics:

During the first infusion of each course, the initial infusion rate of 50 mg/hour can be escalated in 50 mg increments every 30 minutes to a maximum rate of 400 mg/hour.

During the second infusion of each course, the initial rate of 100 mg/hour can be escalated in 100 mg increments every 30 minutes to a maximum rate of 400 mg/hour.

References: Summary of Product Characteristics

There is currently no experience with MabThera^® in patients with RA with previous hepatitis B. Based on reported reactivation of hepatitis B in patients with NHL, the US package insert recommends the screening of patients with a high risk of hepatitis B infection before starting treatment. Of note, the American College of Rheumatology also recommends screening patients with RA for hepatitis prior to MabThera^® initiation.

In RA clinical trials, no case of hepatitis B reactivation has been observed, however patients were pre-screened for HBV. One patient with RA developed a de novo hepatitis B infection 4 months after administration of the first dose of MabThera^®. This resolved without complication following treatment with lamivudine.

In the oncology setting, while both the underlying disease and the concomitant chemotherapy are confounding factors, very rare cases of hepatitis B reactivation (including reports of fulminant hepatitis) have been reported in patients treated with MabThera^®; the majority of these patients were also receiving chemotherapy.

References: ACR hotline, May 2006; Rituxan Prescribing Information

In the REFLEX Phase III study MabThera^® was shown to be effective in patients who were unresponsive to one or more tumour necrosis factor (TNF) inhibitors. A variety of TNF inhibitor therapies are currently available, however large observational studies suggest that the efficacy of TNF inhibitors may decline following switching to a second or third drug of this class. When a patient has failed a TNF inhibitor, B cell therapy should be considered based on longitudinal registry data suggesting that MabThera^® offers significantly greater improvements in RA disease activity compared with an alternative TNF inhibitor. This suggests that switching to a biologic agent of a different class, such as MabThera^®, after an inadequate response to a TNF inhibitor may be more effective than switching to an alternative TNF inhibitor.

Reference: Cohen et al., 2006; Gomez-Reino & Carmona, 2006; Karlsson et al., 2008; Finckh et al., 2007

Pre-medication with intravenous glucocorticoids (methylprednisolone 100 mg or its equivalent) has been shown to significantly reduce both the frequency and the severity of acute infusion reactions and is therefore recommended before each infusion of MabThera^®. Oral glucocorticoids provide no additional benefit.

Reference: Emery et al. 2006

There is currently no experience with the use of MabThera^® in patients with RA and previous hepatitis C. In other indications, the effect of MabThera^® on patients with prior hepatitis C is unclear. Screening for hepatitis C might be considered before MabThera^® treatment initiation in high-risk patients based on the treating physician’s opinion.

In RA clinical trials, patients were screened for hepatitis C antibodies before study entry.

Hepatitis C has been reported to be associated with various autoimmune diseases. A number of case reports and small studies have been published that assess the efficacy and safety of MabThera^® in some of these disease areas. In patients with hepatitis C-related autoimmune disease, the impact of MabThera^® treatment on hepatitis C viral load produced conflicting results, with either a minimal change or decrease in fluctuation of viral load, or an increase in viral load.

References: Aksoy et al. 2006; Roccatello et al. 2004; Sansonno et al. 2003; Weitz 2005; Zaja et al. 2003

If a patient experienced an infusion reaction during the first infusion, the patient needs to be carefully monitored during subsequent infusions. In such a case, the initial rate of the second infusion should be the same as for the first infusion.

The initial rate of 50 mg/hour can be escalated in 50 mg increments every 30 minutes to a maximum rate of 400 mg/hour.

No opportunistic infections have been reported to date in RA clinical studies.

Unlike TNF inhibitor therapies, MabThera^® acts by depleting B cells and has no effect on granuloma stabilisation.

No cases of TB reactivation have been reported during the entire MabThera^® RA clinical development programme.

MabThera^® has been used in the treatment of more than 730,000 oncology patients without major safety concerns. In these patients, there is no evidence to date of an increased risk of TB reactivation.

The first signs of response are usually seen 4–8 weeks following the first infusion of MabThera^® in clinical trials. Maximal response is generally achieved from 16 weeks.

References: Emery et al. 2006; Cohen et al. 2006

The duration of response to just 2 infusions of MabThera^® given 2 weeks apart is unprecedented – the majority of patients have a response that lasts for at least 6 months. Although extended therapeutic efficacy is seen in a small subset of patients for up to 12 months or longer, most patients lose their response between 6 and 12 months following the initial course of MabThera^® and require a repeat course at this time.

There are no clinical or biological markers that have been identified to date that can be used to predict the precise duration of effect of MabThera^® in individual patients.

Pharmacokinetic and pharmacodynamic data support the consideration of 6 months as a time marker for repeat treatment with MabThera^®. At 6 months, MabThera^® blood levels are below the limit of detection and the start of peripheral B cell return (repletion) is also apparent, although this is not necessarily predictive of a return of symptoms.

References: Breedveld et al. 2007; Cohen et al. 2006; Edwards et al. 2004; Edwards et al. 2005; Emery et al. 2006; Magrini et al. 2005